Striking a Nerve: CSF Tau Test Comes of Age for CJD

A cerebrospinal fluid test that may improve on current methods for confirming a diagnosis of Creutzfeldt-Jakob disease (CJD) appears to have passed what could be the most definitive evaluation possible.

Swedish researchers, using national registry data covering nearly 10,000 people who had cerebrospinal fluid (CSF) samples tested for levels of total and phosphorylated tau protein (t- and p-tau, respectively), found that levels of t-tau and the t-tau/p-tau ratio were moderately sensitive and highly specific for CJD versus other progressive dementias including Alzheimer's disease.

Using a previously developed algorithm for combining t-tau levels and the t-tau/p-tau ratio, the researchers -- led by Tobias Skillbäck, MD, of the University of Gothenburg in Sweden -- found overall sensitivity of 78.5% and specificity of 99.0% for CJD diagnosis using these markers, according to a report online in JAMA Neurology.

CJD is marked by sponge-like brain atrophy and rapidly progressing dementia, and is thought to originate with abnormally folded prion proteins. Although the rogue prions are transmissible and occur in other species, such as cattle, most CJD cases arise spontaneously from misfolding of a normal prion protein, which then catalyzes refolding of other prions into the disease-causing form.

According to current guidelines issued by the American Academy of Neurology, CJD should be diagnosed primarily on the basis of clinical symptoms and imaging findings, but can be supplemented by CSF testing for another marker, called the 14-3-3 protein. That recommendation came from a meta-analysis indicating a sensitivity of 92% and specificity of 80% for the protein.

The recommendation came with a caution that the 14-3-3 test was not specific enough to rule out other, more treatable causes of patients' symptoms. And more doubt on its diagnostic value was cast in an Italian study published last year, which found a specificity of just 43% -- meaning that more than half of positive results were false.

Levels of tau protein, on the other hand, have attracted increasing interest as markers of CJD. As Skillbäck and colleagues explained, t-tau levels correspond to rates of axonal damage in various neurological diseases, whereas p-tau is increased in Alzheimer's disease but not other dementias.

As a CJD marker, the hypothesis is that t-tau would be elevated relative to levels seen in healthy people, whereas p-tau levels would not be elevated.

The hypothesis was also borne out in the new Swedish study. Skillbäck and colleagues defined a result positive for CJD when the t-tau level was 1,400 ng/mL or higher and the t-tau/p-tau ratio was greater than 25.

Comparing marker levels in the CJD cases versus those with Alzheimer's disease diagnosis, a positive result for CJD was nearly 200 times more likely to reflect a true positive than a misdiagnosed Alzheimer's disease case. In comparison with other dementias, this "positive likelihood ratio" exceeded 100.

An earlier study by Dutch researchers had found that t- and p-tau, along with a form of beta-amyloid protein, in CSF could distinguish a variety of dementias, including CJD, from each other. However, that study was small, with just six CJD patients and about 1,700 overall. Skillbäck and colleagues had data for 93 CJD cases.

Given the rarity of CJD -- about one or two new cases per million population annually -- a sizable prospective study of a proposed CJD diagnostic would be next to impossible.

Thus, their registry-based study of nearly 10,000 individuals is likely to be the best that can be expected. The evidence for the 14-3-3 protein test came from similar studies, so the odds that tau-based testing for CJD may gain official endorsement look pretty good at this point.

Skillbäck and colleagues noted, though, that the specific cutoffs they used might not be optimal for other populations or in labs using different assays for CSF tau levels. They also acknowledged that autopsy confirmation of CJD was not done in more than half of their cases.

Striking a Nerve is a blog by John Gever for readers interested in neurology and psychiatry.

The Swedish study was funded by the Swedish Research Council and a variety of foundations. Study authors declared they had no relevant financial interests.

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